A stimulus actuated polymeric device for the prolonged therapeutic management of moderate to severe chronic pain

Abstract:

Chronic pain may be defined as pain which persists in a patient for a prolonged period of time.
Although this period of time may range from 3-12 months, it is most commonly described as pain
which extends beyond the time required for healing. Chronic pain may also be classified into two
different categories depending on the cause. The first category is nociceptive, which is chronic pain
caused by activation of nociceptors. This may be due to several factors such as trauma or
temperature. The second category is neuropathic chronic pain. These are chronic pains which are not
necessarily caused by trauma, but more likely due to the malfunction of the nervous system. For this
study, our aim is to develop a patient-controlled, externally actuated hydrogel system which is capable
of ‘ON-OFF’ drug release. The model drug which was incorporated into the SAPD was a Non-
Steroidal Anti-Inflammatory Drugs (NSAID), and thus our drug release system would be beneficial
primarily for nociceptive chronic pain. This subcutaneously implanted SAPD is produced with an
electroactive polymer which allows drug release in the presence of electrical stimulation. This would
result in direct availability of drug at the site of actuation with reduced side-effects and increased drug
bio-availability.
The SAPD was formed by crosslinking polyvinyl alcohol (PVA) with diethyl acetamidomalate (DAA).
The result was a hydrogel which was capable of swelling while remaining insoluble when placed in
various solvents. After the hydrogel was synthesized, indomethacin was incorporated as the model
drug. Indomethacin exhibited superior Drug Entrapment Efficiency (DEE) (±70-90%) and responsive
release in the presence of an electrical stimulus. Finally, polyaniline (PANi) was used as the
electroactive polymer in order to enhance the conductivity and allow sufficient release of the drug.
Optimization of the SAPD was undertaken with a 3-factor Box-Behnken Design which measured the
rate of erosion, drug release and DEE. The optimized SAPD was synthesized using PVA (0.8g)
crosslinked with DAA (0.0689g) and a concentration of 1.3418%w/w PANi. Indomethacin was used and
the DEE achieved was 76.32±10.46% (target 80.5381%). The drug release profile was
1.622%±0.1857% (target 1.7%) per release cycle and erosion rate was 5.73±1.26% (target 6.3201%)
when actuated with a potential difference of 1V for a duration of 1 minute.
Chemometric modelling performed on the SAPD showed that drug release may be attributed to
erosion of the SAPD in the presence of an electrical stimulus. The polymeric strands usually rest as a
coiled state within the SAPD. This coiled state may be the reason the hydrogel remained intact in the
absence of electrical stimulation. However, external electrical fields may adduct to form a coil rather
than an extended chain resulting in the formation of a globular aniline-vinyl complex. This formation
thus leads to a weakened form of the hydrogel structure, resulting in breakdown and ultimately
erosion. This erosive phenomenon ceased once the electrical stimulation was removed. The end
result of this hydrogel erosion is the liberation of the entrapped indomethacin.
In vivo animal studies on the SAPD indicated an ‘ON-OFF’ drug release profile. The drug release was
consistent and drug quantity of ±0.15mg per release cycle in the Sprague-Dawley rat model. The
SAPD was implanted subcutaneously under the left flank and an electrical stimulation was triggered
with the use of a 2-in-1 galvano/potentiostat in order to ensure the electrical stimulus was constant.
The potential difference used was 1V over a period of 1 minute. The rats were assessed for signs of
illness or swelling after the implantation procedure to determine the biocompatibility of the SAPD. The
rats were monitored for 10 days and weighed daily. Results have shown that the rats did not
experience any considerable swelling and the weights of each rat were steady, thus indicating
biocompatibility of the SAPD. Histopatholgical samples indicated mild inflammation around the site of
implantation 10 days after implantation. This may have been due to minor surgery at site of
implantation. The biocompatibility of the SAPD was generally good and there were no signs of tumour
or long term tissue inflammation. Future application of the SAPD may include an external actuation
device to be worn as a watch which allows actuation of the SAPD when required by the patient.